Hutchens Martha A, Luker Kathryn E, Sonstein Joanne, Núñez Gabriel, Curtis Jeffrey L, Luker Gary D
Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
PLoS Pathog. 2008 Sep 19;4(9):e1000153. doi: 10.1371/journal.ppat.1000153.
Innate immune responses are essential for controlling poxvirus infection. The threat of a bioterrorist attack using Variola major, the smallpox virus, or zoonotic transmission of other poxviruses has renewed interest in understanding interactions between these viruses and their hosts. We recently determined that TLR3 regulates a detrimental innate immune response that enhances replication, morbidity, and mortality in mice in response to vaccinia virus, a model pathogen for studies of poxviruses. To further investigate Toll-like receptor signaling in vaccinia infection, we first focused on TRIF, the only known adapter protein for TLR3. Unexpectedly, bioluminescence imaging showed that mice lacking TRIF are more susceptible to vaccinia infection than wild-type mice. We then focused on TLR4, the other Toll-like receptor that signals through TRIF. Following respiratory infection with vaccinia, mice lacking TLR4 signaling had greater viral replication, hypothermia, and mortality than control animals. The mechanism of TLR4-mediated protection was not due to increased release of proinflammatory cytokines or changes in total numbers of immune cells recruited to the lung. Challenge of primary bone marrow macrophages isolated from TLR4 mutant and control mice suggested that TLR4 recognizes a viral ligand rather than an endogenous ligand. These data establish that TLR4 mediates a protective innate immune response against vaccinia virus, which informs development of new vaccines and therapeutic agents targeted against poxviruses.
先天免疫反应对于控制痘病毒感染至关重要。使用天花病毒（即痘苗病毒）进行生物恐怖袭击的威胁，或其他痘病毒的人畜共患病传播，重新引发了人们对了解这些病毒与其宿主之间相互作用的兴趣。我们最近确定，Toll样受体3（TLR3）调节一种有害的先天免疫反应，这种反应会增强小鼠对痘苗病毒（一种用于痘病毒研究的模型病原体）感染的复制、发病率和死亡率。为了进一步研究痘苗病毒感染中的Toll样受体信号传导，我们首先聚焦于TRIF，它是TLR3唯一已知的衔接蛋白。出乎意料的是，生物发光成像显示，缺乏TRIF的小鼠比野生型小鼠更容易受到痘苗病毒感染。然后我们聚焦于TLR4，它是另一种通过TRIF发出信号的Toll样受体。在经呼吸道感染痘苗病毒后，缺乏TLR4信号传导的小鼠比对照动物有更高的病毒复制、体温过低和死亡率。TLR4介导的保护机制并非由于促炎细胞因子释放增加或募集到肺部的免疫细胞总数变化。对从TLR4突变小鼠和对照小鼠分离的原代骨髓巨噬细胞进行攻击试验表明，TLR4识别的是病毒配体而非内源性配体。这些数据表明，TLR4介导针对痘苗病毒的保护性先天免疫反应，这为开发针对痘病毒的新型疫苗和治疗药物提供了依据。
